De novo and recurrent metastatic breast cancer - A systematic review of population-level changes in survival since 1995.

BACKGROUND: Advances in breast cancer (BC) care have reduced mortality, but their impact on survival once diagnosed with metastasis is less well described. This systematic review aimed to describe population-level survival since 1995 for de novo metastatic BC (dnMBC) and recurrent MBC (rMBC). METHODS: We searched MEDLINE 01/01/1995-12/04/2021 to identify population-based cohort studies of MBC reporting overall (OS) or BC-specific survival (BCSS) over time. We appraised risk-of-bias and summarised survival descriptively for MBC diagnoses in 5-year periods from 1995 until 2014; and for age, hormone receptor and HER2 subgroups. FINDINGS: We identified 20 eligible studies (14 dnMBC, 1 rMBC, 5 combined). Potential sources of bias in these studies were confounding and shorter follow-up for the latest diagnosis period.For dnMBC, 13 of 14 studies reported improved OS or BCSS since 1995. In 2005-2009, the median OS was 26 months (range 24-30), a median gain of 6 months since 1995-1999 (range 0-9, 4 studies). Median 5-year OS was 23% in 2005-2009, a median gain of 7% since 1995-1999 (range -2 to 14%, 4 studies). For women ≥70 years, the median and 5-year OS was unchanged (1 study) with no to modest difference in relative survival (range: -1·9% (p = 0.71) to +2·1% (p = 0.045), 3 studies). For rMBC, one study reported no change in survival between 1998 and 2006 and 2007-2013 (median OS 23 months). For combined MBC, 76-89% had rMBC. Three of four studies observed no change in median OS after 2000. Of these, one study reported median OS improved for women ≤60 years (1995-1999 19·1; 2000-2004 22·3 months) but not >60 years (12·7, 11·6 months). INTERPRETATION: Population-level improvements in OS for dnMBC have not been consistently observed in rMBC cohorts nor older women. These findings have implications for counselling patients about prognosis, planning cancer services and trial stratification. FUNDING: SL was funded in part by a National Health and Medical Research Council (NHMRC) Project Grant ID: 1125433. NH was funded by the NBCF Chair in Breast Cancer Prevention grant (EC-21-001) and a NHMRC Investigator (Leader) grant (194410). BD and SAP were funded in part by the NHMRC Centre of Research Excellence in Medicines Intelligence (1196900).

TB testing in HIV-positive patients prior to antiretroviral treatment.

BACKGROUND: TB diagnosis in patients with HIV is challenging due to the lower sensitivities across tests. Molecular tests are preferred and the Xpert® MTB/RIF assay has limitations in lower-income settings. We evaluated the performance of loop-mediated isothermal amplification (LAMP) and the lipoarabinomannan (LAM) test in HIV-positive, ART-naïve clinic patients.METHODS: A total of 783 eligible patients were enrolled; three spot sputum samples of 646 patients were tested using TB-LAMP, Xpert, smear microscopy and culture, while 649 patients had TB-LAM testing. Sensitivity, specificity, and negative and positive predictive values were estimated with 95% confidence intervals.RESULTS: Sensitivities for smear microscopy, TB-LAMP and Xpert were respectively 50%, 63% and 74% compared to culture, with specificities of respectively 99.2%, 98.5% and 97.5%. An additional eight were positive on TB-LAM alone. Seventy TB patients (9%) were detected using standard-of-care testing, an additional 27 (3%) were detected using study testing. Treatment was initiated in 57/70 (81%) clinic patients, but only in 56% (57/97) of all those with positive TB tests; 4/8 multidrug-resistant samples were detected using Xpert.CONCLUSION: TB diagnostics continue to miss cases in this high-burden setting. TB-LAMP was more sensitive than smear microscopy, and if followed by culture and drug susceptibility testing as required, can diagnose TB in HIV-positive patients. TB-LAM is a useful add-in test and both tests at the point-of-care would maximise yield.

A rapid review of the effectiveness of screening practices at airports, land borders and ports to reduce the transmission of respiratory infectious diseases such as COVID-19.

BACKGROUND: Travel screening for infectious diseases is often implemented to delay or prevent the entry of infected persons to a country/area. OBJECTIVES: To evaluate the effectiveness of different point-of-entry screening strategies in achieving a reduction in imported COVID-19 transmission. METHODS: A rapid evidence review was conducted, systematically searching PubMed and Google Scholar and grey literature on 27 March 2020. RESULTS: We screened 1 194 records. Nine potential full-text articles were assessed for eligibility and included. Three articles investigated the effectiveness of entry-based thermal and body temperature scanning. Entry-based infrared thermal or body temperature scanning for COVID-19 was unlikely to be effective. Two systematic reviews found no additional benefit of travel restrictions/screening. In a COVID-19 modelling study, airport screening was not effective, with exit and entry thermal scanning identifying half and missing almost half of infected travellers. Two other modelling studies found that entry-based travel screening would achieve only modest delays in community transmission, while international travel quarantine could reduce case importations by 80%. CONCLUSIONS: There is insufficient evidence to support entry and exit screening at points of entry, as these strategies detect just over half of the infected cases, missing almost half at entry points. The benefits of airport screening therefore need to be context specific and weighed against the resources and cost of implementation, the contribution of imported cases to total cases, and the benefits of identifying 50% of cases in the South African context with the country's high HIV and tuberculosis prevalence and limited resources to deal with a pandemic of this nature.

A rapid review of the effectiveness of screening practices at airports, land borders and ports to reduce the transmission of respiratory infectious diseases such as COVID-19

Background. Travel screening for infectious diseases is often implemented to delay or prevent the entry of infected persons to a country/area.Objectives. To evaluate the effectiveness of different point-of-entry screening strategies in achieving a reduction in imported COVID-19 transmission.Methods. A rapid evidence review was conducted, systematically searching PubMed and Google Scholar and grey literature on 27 March 2020.Results. We screened 1 194 records. Nine potential full-text articles were assessed for eligibility and included. Three articles investigated the effectiveness of entry-based thermal and body temperature scanning. Entry-based infrared thermal or body temperature scanning for COVID-19 was unlikely to be effective. Two systematic reviews found no additional benefit of travel restrictions/screening. In a COVID-19 modelling study, airport screening was not effective, with exit and entry thermal scanning identifying half and missing almost half of infected travellers. Two other modelling studies found that entry-based travel screening would achieve only modest delays in community transmission, while international travel quarantine could reduce case importations by 80%.Conclusions. There is insufficient evidence to support entry and exit screening at points of entry, as these strategies detect just over half of the infected cases, missing almost half at entry points. The benefits of airport screening therefore need to be context specific and weighed against the resources and cost of implementation, the contribution of imported cases to total cases, and the benefits of identifying 50% of cases in the South African context with the country's high HIV and tuberculosis prevalence and limited resources to deal with a pandemic of this nature

Implementation of the flipped residency research model to enhance residency research training.

PURPOSE: The attainment of fundamental research skills to create and disseminate new knowledge is imperative for the advancement of pharmacy practice. Research training is an important component of postgraduate residency training; however, the traditional model of performing residency research has several limitations that have hindered the ability of residents to complete high-quality research projects. Therefore, our institution developed and implemented the flipped residency research model with the 2013-2014 pharmacy practice residency class. SUMMARY: The flipped residency research model modifies the research timeline to better align research activities with residents' abilities at specific time points during the year. In the 4 years following implementation of the flipped residency research model, our institution found improvements in a number of areas pertaining to the research process compared with an evaluation of the 7 years prior to implementation. A decrease in the number of reviews required from institutional review boards was observed, resulting in improved institutional review board efficiency. The flipped residency research model also addressed limitations surrounding manuscript development and submission, as demonstrated by an improved publication rate. Additionally, residents who participated in the flipped residency research model self-reported increased comfort with research-related abilities associated with study design, implementation, manuscript development and submission, and biostatistics. CONCLUSION: The modified research timeline of the flipped residency research model better aligns research activities with resident experiences and abilities. This realignment has translated to demonstrable impact in the success of residency projects and dissemination of results. Research is needed to investigate the impact of the flipped residency research model on longer term scholarly success.

Identifying incident cancer cases in dispensing claims: A validation study using Australia's Repatriation Pharmaceutical Benefits Scheme (PBS) data.

INTRODUCTION: Dispensing claims are used commonly as proxy measures in pharmacoepidemiological studies; however, their validity is often untested. OBJECTIVES: To assess the performance of a proxy for identifying cancer cases based on the dispensing of anticancer medicines and estimate the misclassification of cancer status and potential for bias researchers may encounter when using this proxy. METHODS: We conducted our validation study using Department of Veterans' Affairs (DVA) client data linked with the New South Wales (NSW) Cancer Registry and Repatriation Pharmaceutical Benefits Scheme data. We included DVA clients aged ≥65 years residing in NSW between July 2004 and December 2012. We matched clients with a cancer diagnosis to clients without a diagnosis based on demographic characteristics and available observation time. We used dispensing claims for anticancer medicines dispensed between July 2004 and December 2013 as a proxy to identify clients with cancer and calculated sensitivity, specificity, positive predictive values and negative predictive values compared with cancer registrations (gold standard), overall and by cancer site. We illustrated misclassification by the proxy in a cohort of people initiating opioid therapy. Using the proxy, we excluded people with cancer from the cohort, in an attempt to delineate people potentially using opioids for cancer rather than chronic non-cancer pain. RESULTS: We identified 15,679 new cancer diagnoses in 14,112 DVA clients from the cancer registry and 62,663 clients without a diagnosis. Sensitivity of the proxy based on dispensing claims was 30% for all cancers and around 20% for specific cancers (range: 10-67%). Specificity was above 90% for all cancers. The dispensing proxy correctly identified 26% of people with a cancer diagnosis who initiated opioid therapy and failed to identify 74% those with a cancer diagnosis; the proxy was most robust for clients with breast cancer where 61% were correctly identified by proxy. CONCLUSIONS: Using dispensing of anticancer medicines to identify people with a cancer diagnosis performed poorly. Excluding patients with evidence of anticancer medicine use from cohort studies may result removal of a disproportionate number of women with breast cancer. Researchers excluding or otherwise using anticancer medicine dispensing to identify people with cancer in pharmacoepidemiological studies should acknowledge the potential biases introduced to their findings. KEYWORDS: cancer, diagnosis, proxy, dispensing records, validation study.

ROR1 and ROR2 play distinct and opposing roles in endometrial cancer.

OBJECTIVE: In recent years, the Wnt signalling pathway and the ROR1 and ROR2 receptors have been implicated in a range of gynecological cancers. These receptors have been described as prospective therapeutic targets, and this study investigated such potential in an endometrial cancer context. METHOD: Immunohistochemistry for ROR1 and ROR2 was performed in a patient cohort, and expression was correlated with clinicopathological parameters including type, stage, grade, myometrial invasion, lymphovascular involvement, patient age and survival. The functional role of these receptors in endometrial cancer was investigated via siRNA knockdown of ROR1 and ROR2 in three cell line models (KLE, RL95-2 and MFE-319). Effects on proliferation, adhesion, migration and invasion were measured. RESULTS: High ROR1 expression in patient samples correlated with worse overall survival (p = 0.0169) while high ROR2 expression correlated with better overall survival (p = 0.06). ROR1 knockdown in KLE cells significantly decreased proliferation (p = 0.047) and reduced migration and invasion. ROR2 knockdown in RL95-2 cells increased cell migration and invasion (p = 0.011). Double ROR1 and ROR2 knockdown in MFE-319 cells decreased adhesion and significantly increased cell migration (P = 0.008) and invasion (p < 0.001). CONCLUSION: ROR1 and ROR2 play distinct roles in endometrial cancer. ROR1 may promote tumor progression, similar to its role in ovarian cancer, while ROR2 may act as a tumor suppressor in endometrioid endometrial cancer, similar to its role in colorectal cancer. With several ROR-targeting therapies currently in development and phase I clinical trials for other tumor types, this study supports the potential of these receptors as therapeutic targets for women with endometrial cancer.

Viral sensing at the blood-brain barrier: new roles for innate immunity at the CNS vasculature.

Neurotropic viral infections are a major source of disease worldwide and represent a growing burden to public health. While the central nervous system (CNS) is normally protected from viral infection by the blood-brain barrier (BBB), many viruses are able to cross the BBB and establish CNS infection through processes that largely remain poorly understood. A growing body of recent research has begun to shed light on the viral and host factors that modulate BBB function, contributing to both protective and pathological disease processes. Central to these studies have been the actions of host cytokines and chemokines, which have increasingly been shown to be key regulators of BBB physiology. This review summarizes recent advances in understanding how BBB function governs both viral pathogenesis and host immune responses during neurotropic viral infections.

Expression of the novel Wnt receptor ROR2 is increased in breast cancer and may regulate both ß-catenin dependent and independent Wnt signalling.

PURPOSE: Wnt signalling has been implicated in breast cancer, and in particular aberrant ß-catenin-independent Wnt signalling has been associated with breast cancer metastasis and Tamoxifen resistance. Despite Wnt pathway involvement in many human cancers, attempts to target the pathway therapeutically have been disappointing. The recent discovery that the receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a novel Wnt receptor provides a potential new therapeutic and diagnostic target. METHODS: To clarify the role of ROR2 in breast cancer, we investigated its expression via ROR2 immunohistochemistry in a clinical cohort of breast cancer patients, and via in vitro studies incorporating both overexpression and knock-down of ROR2. RESULTS: ROR2 was expressed in the majority of breast cancer patients (87%), including those classed as triple negative. Breast cancer patients expressing ROR2 had a significantly shorter overall survival than those lacking ROR2 expression (P < 0.05). Overexpression of ROR2 in the mammary epithelial cell line, MCF10A, increased both ß-catenin-dependent and ß-catenin-independent targets and decreased cell adhesion. Knock-down of ROR2 in the breast cancer cell lines, MDA-MB-453 and HCC1143, decreased both ß-catenin-dependent and ß-catenin-independent targets and increased cell adhesion. Treatment of ROR2-expressing breast cancer cells with the novel berberine derivative, NAX53, significantly inhibited cell proliferation and migration. CONCLUSIONS: This is the first study to report the expression of ROR2 in breast cancer. Breast cancer patients expressing ROR2 had a significantly worse prognosis than those lacking ROR2. ROR2 may regulate both ß-catenin-dependent and ß-catenin-independent Wnt signalling pathways, and represents a potential diagnostic and therapeutic target.

Second cancers and late mortality in Australian children treated by allogeneic HSCT for haematological malignancy.

We examined risk of second cancer and late mortality in a population-based Australian cohort of 717 pediatric allogeneic stem cell transplant (HSCT) recipients treated for a malignant disease during 1982-2007. Record linkage with population-based death and cancer registries identified 17 second cancers at a median of 7.9 years post HSCT; thyroid cancer being the most common malignancy (n=8). The cumulative incidence of second cancer was 8.7% at follow-up, and second cancers occurred 20 times more often than in the general population (standardised incidence ratio 20.3, 95% confidence interval (CI)=12.6-32.7). Transplantation using radiation-based conditioning regimens was associated with increased second cancer risk. A total of 367 patients survived for at least 2 years post HSCT and of these 44 (12%) died at a median of 3.1 years after HSCT. Relapse was the most common cause of late mortality (n=32). The cumulative incidence of late mortality was 14.7%. The observed rate of late mortality was 36 times greater than in the matched general population (standardised mortality ratio 35.9, 95% CI=26.7-48.3). Recipients who relapsed or who had radiation-based conditioning regimens were at higher risk of late mortality. Second cancers and late mortality continue to be a risk for pediatric patients undergoing HSCT, and these results highlight the need for effective screening and survivorship programs.

The use of complementary and alternative medicine by women transitioning through menopause in Germany: results of a survey of women aged 45-60 years.

OBJECTIVES: To describe prevalence rates of complementary and alternative medicine therapies (CAM) for the relief of menopausal complaints among German women. Furthermore, to investigate the perceived effectiveness of these therapies. DESIGN: A self-administered questionnaire was sent to 9785 randomly selected women in Germany aged between 45 and 60 years. RESULTS: A total of 1893 (19.3%) questionnaires have been sent back. The mean age of all participants was 52.6±4.3 years. 81% (n=1517) of the responding women stated that they had experienced menopausal complaints at least once. Symptoms ranged from vasomotor symptoms, including hot flushes and night sweats, in 71.2% of cases, to bladder problems in 42.7%. The average symptom score (MRS II total score, range 1-44) among the respondents was 12.76±9.6. More than half (56%; n=1049/1872) of the responding women had used some form of therapy to alleviate their symptoms at least once. The majority of women undertaking a therapy (64.8%; n=679/1049) had used only CAM interventions (either one or more type of CAM), 14.2% (n=149) had used hormone replacement therapy (HRT) only, while 21.1% (n=221/1049) had tried both CAM and HRT. Popular CAM interventions by the respondents were an alteration of lifestyle (28.7%), St. John's wort (18.3%) and homoeopathy (14.9%). An alteration in lifestyle was rated as the most effective CAM treatment with 84.9% (n=457). Other treatments like hormone yoga (79.2%; n=42), homoeopathy (73.7%; n=205) and TCM (59.1%; n=94) were also perceived to be effective. Phytoestrogens were rated as the most ineffective (45.5%; n=50). CONCLUSION: CAM interventions to alleviate menopausal complaints are popular among German women, with 48.2% (n=900/1872) of respondents reporting having used CAM either alone or in combination with HRT. However, the users rated the effects of CAM differently, with some reporting CAM to be highly effective, while others indicate lower effectiveness. Nevertheless, women with a significantly higher symptom scoring tend to use both CAM and a conventional therapy (HRT).

Second cancer risk in adults receiving autologous haematopoietic SCT for cancer: a population-based cohort study.

Population-based evidence on second cancer risk following autologous haematopoietic SCT (HCT) is lacking. We quantified second cancer risk for a national, population-based cohort of adult Australians receiving autologous HCT for cancer and notified to the Australasian Bone Marrow Transplant Recipient Registry 1992-2007 (n=7765). Cancer diagnoses and deaths were ascertained by linkage with the Australian Cancer Database and National Death Index. Standardized incidence ratios (SIRs) were calculated and Cox regression models were used to estimate within-cohort risk factors treating death as a competing risk. During a median 2.5 years follow-up, second cancer risk was modestly increased compared with the general population (SIR 1.4, 95% confidence interval 1.2-1.6); significantly elevated risk was also observed for AML/myelodysplastic syndrome (SIR=20.6), melanoma (SIR=2.6) and non-Hodgkin lymphoma (SIR=3.3). Recipients at elevated risk of any second cancer included males, and those transplanted at a younger age, in an earlier HCT era, or for lymphoma or testicular cancer. Male sex, older age (>45 years) and history of relapse after HCT predicted melanoma risk. Transplantation for Hodgkin lymphoma and older age were associated with lung cancer risk. Second malignancies are an important late effect and these results inform and emphasize the need for cancer surveillance in autologous HCT survivors.

Attitude of German women towards hormone therapy: results of a lay survey.

OBJECTIVE: Hormone therapy (HT) use has experienced a substantial change since publication of Women's Health Initiative (WHI) controlled trial. We aimed to investigate the attitude towards HT in German women aged 45-60 years. STUDY DESIGN: A questionnaire was sent to 9785 randomly selected women in Germany aged between 45 and 60 years. RESULTS: Response rate was 19.3% (n = 1,893). Of those, 81% experienced climacteric symptoms. Vasomotor symptoms were most frequently reported (71.2%; n = 1332). Of the respondents, 19.7% (n = 369) used HT. The most frequently mentioned benefits of HT were the improvement of climacteric complaints (71.2%; n = 1346), followed by the relief of osteoporosis (37.2%; n = 697) and the "anti-aging" effect (16.3%; n = 305). Breast cancer was stated as the main risk (64.9%; n = 1215), closely followed by weight gain (53.4%; n = 1000) and thromboembolism (48%; n = 898). About 44% of the women who has been advised by gynaecologists choose a HT, whereas this rate dropped down to 14.3% and 11.3% for women who have been advised by friends or media. CONCLUSION: German women were generally aware of the main risks and benefits of HT. "More informed" women appear to be more likely to use HT compared to "less informed" women. The media produces negative impression of HT.

High frequency of vitamin D deficiency in ambulatory HIV-Positive patients.

Several reports have suggested an increased prevalence of osteopenia and osteoporosis in HIV-infected individuals. Vitamin D deficiency may be a risk factor for osteoporosis and bone fractures. We aimed to determine the prevalence of vitamin D insufficiency in an outpatient HIV clinic in Boston. We collected serum levels of 25-OH vitamin D and evaluated calcium and vitamin D intake in adult HIV-positive outpatients during the winter and spring of 2005. Fifty-seven subjects were enrolled. The prevalence of moderate (< or = 20 and>10 ng/ml) and severe (< or =10 ng/ml) 25-OH vitamin D deficiency was 36.8% and 10.5%, respectively. Lower vitamin D intake was significantly associated with severe 25-OH vitamin D deficiency (p=0.01). Lactose intolerance tended to be associated with severe vitamin D deficiency (p=0.08). Antiretroviral use and low daily calcium intake were significantly associated with elevated parathyroid hormone levels (p=0.01 and 0.03, respectively). Vitamin D deficiency was frequent in ambulatory HIV-positive patients. HIV-infected individuals living in areas with low exposure to ultraviolet light during winter may benefit from vitamin D supplementation.

Mesoscopic statistical properties of multistep enzyme-mediated reactions.

Enzyme-mediated reactions may proceed through multiple intermediate conformational states before creating a final product molecule, and one often wishes to identify such intermediate structures from observations of the product creation. In this study, the authors address this problem by solving the chemical master equations for various enzymatic reactions. A perturbation theory analogous to that used in quantum mechanics allows the determination of the first (n) and the second (σ2) cumulants of the distribution of created product molecules as a function of the substrate concentration and the kinetic rates of the intermediate processes. The mean product flux V=d(n)/dt (or 'dose-response' curve) and the Fano factor F= σ2/(n) are both realistically measurable quantities, and whereas the mean flux can often appear the same for different reaction types, the Fano factor can be quite different. This suggests both qualitative and quantitative ways to discriminate between different reaction schemes, and the authors explore this possibility in the context of four sample multistep enzymatic reactions. Measuring both the mean flux and the Fano factor can not only discriminate between reaction types, but can also provide some detailed information about the internal, unobserved kinetic rates, and this can be done without measuring single-molecule transition events.

Systematic review: the methodological quality of trials affects estimates of treatment efficacy in functional (non-ulcer) dyspepsia.

AIM: To evaluate treatment efficacy using objective quality criteria. METHODS: A systematic review was performed of randomized controlled trials of endoscopically investigated dyspepsia (1979-2003) using the Jadad score and Rome II guidelines. The Jadad score differentiated studies as 'high quality' (score 4-5/5) vs. 'poor quality' (score 1-3/5). Three key Rome II guidelines on study design (cut-off of 0/3 or > 0/3) were also compared with the Jadad score. RESULTS: Poor quality trials suggested a benefit of prokinetic therapy [relative risk (RR) of remaining dyspeptic, 0.47; 95% confidence interval (CI), 0.39-0.56), which was not confirmed in high quality trials (RR, 1.0; 95% CI, 0.84-1.19). There was a marked benefit of H2-receptor antagonist therapy in poor quality trials (RR, 0.68; 95% CI, 0.61-0.76), but a marginal benefit in good quality trials (RR, 0.87; 95% CI, 0.79-0.97). Trial quality did not affect the small statistically significant benefit seen with Helicobacter pylori eradication. Two high quality trials suggested a limited benefit with the use of proton pump inhibitors, with no poor quality trials to provide a comparison. Separation of the studies by the Rome II criteria had a similar impact on the calculated treatment estimates. CONCLUSIONS: The magnitude of benefit of prokinetic and H2-receptor antagonist therapies reported in previous meta-analyses has been over-estimated. The quality of trials has an impact on the efficacy estimates of treatment. The Rome II criteria for study methodology may be appropriate for judging study quality.

Synchronization of coupled rotators: Josephson junction ladders and the locally coupled Kuramoto model.

We show that the resistively shunted junction (RSJ) equations describing a ladder array of overdamped, critical-current disordered Josephson junctions that are current biased along the rungs of the ladder can be mapped onto a Kuramoto model with nearest neighbor, sinusoidal couplings. This result is obtained by an averaging method, in which the fast dynamics of the RSJ equations are integrated out, leaving the dynamics which describe the time scale over which neighboring junctions along the rungs of the ladder phase and frequency synchronize. We quantify the degree of frequency synchronization of the rung junctions by calculating the standard deviation of their time-averaged voltages, sigma(omega), and the phase synchronization is quantified by calculating the time average of the modulus of the Kuramoto order parameter, <|r|>. We test the results of our averaging process by comparing the values of sigma(omega) and <|r|> for the original RSJ equations and our averaged equations. We find excellent agreement for dc bias currents of I(B)/ greater, similar 3, where is the average critical current of the rung junctions, and critical current disorders of up to 10%. We also study the effects of thermal noise on the synchronization properties of the overdamped ladder. Finally, we find that including the effects of junction capacitance can lead to a discontinuous synchronization transition as the strength of the coupling between neighboring junctions is smoothly varied.

Computer-aided vicarious exposure versus live graded exposure for spider phobia in children.

The efficacy of computer-aided vicarious exposure (CAVE) for the treatment of spider phobia in children was evaluated in a single blind, randomised, controlled trial. Twenty-eight participants, aged 10-17 years, received three 45-min sessions of either Live graded exposure (LGE), CAVE or were assigned to a Waitlist. Phobic symptomatology was measured at pre- and post-treatment, and at one month follow-up on a range of behavioural and subjective assessments. The results showed the superiority of the LGE treatment over the CAVE and Waitlist conditions. Effect sizes support CAVE treatment as being superior to the Waitlist and resulting in reductions of phobic symptomatology.

In vivo effect of clarithromycin on multiple cytochrome P450s.

The in vivo effects of oral clarithromycin administration on the in vivo activity of cytochrome P450 1A2, 2C9, and 2D6 were determined. The cytochrome P450 probes caffeine (CYP1A2), tolbutamide (CYP2C9), and dextromethorphan (CYP2D6) were administered as an oral cocktail prior to and 7 days after oral clarithromycin (500 mg twice daily) administration to 12 healthy male subjects. Blood and urine samples were collected and assayed for each of the compounds and their metabolites using high-performance liquid chromatography. The CYP1A2 indices, oral caffeine clearance (6.2 +/- 3.3 l/h before and 5.7 +/- 4.2 l/h after, p > 0.05) and the 6-h paraxanthine to caffeine serum concentration ratio (0.49 +/- 0.3 before and 0.44 +/- 0.3 after, p > 0.05), were unchanged following clarithromycin dosing. Neither the tolbutamide oral clearance (0.77 +/- 0.28 l/h before and 0.72 +/-0.24 l/h after, p > 0.05) nor the tolbutamide urinary metabolic ratio (779 +/- 294 before and 681 +/- 416 after, p > 0.05) indices of CYP2C9 were altered by clarithromycin administration. In the case of CYP2D6, the dextromethorphan to dextrorphan urinary ratio was not significantly different before (0.021 +/- 0.04) and after (0.024 +/- 0.06) clarithromycin dosing. In conclusion, clarithromycin does not appear to alter the in vivo catalytic activity of CYP1A2, CYP2C9, and CYP2D6 in healthy individuals as assessed by caffeine, tolbutamide, and dextromethorphan, respectively.